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PHL. 313

Dr. Khairy Zoheir

Lab.1INTRODUCTION TO NS PHARMACOLOGY and DOSE- RESPONSE CURVE

Nervous System

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Central Nervous System

Brain stem

Cerebrum

Spinal cord

Peripheral Nervous System

Afferent Efferent Sensory division Autonomic

Somatic

Afferent and efferent neurons

• Afferent is known as sensory or receptor neurons which carry nerve impulses from receptors or sense organs toward the central nervous system.

• Efferent is known as motor or effector neurons which carry nerve impulses away from the central nervous system to effectors such as muscles or glands

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The Peripheral Nervous System

Somatic nervous system

(voluntary)

Skeletal muscle

Autonomic nervous system

(involuntary)

Heart, blood vessels,glands, other visceralorgans, smooth muscle

Efferent nervous system

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Anatomic classification

1- sympathetic (fight and flight)

To maintain homeostasis

2- Parasympathetic (rest and digest)

• Its actions can be summarized as "rest and digest", as opposed to the "fight-or-flight" effects of the sympathetic nervous system..

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Neurotransmitter:A chemical that transmits signals from one neuron to another

or from a neuron to an effector cell.

ElectricalStimulation

(impulse)

Chemical(neurotransmitter)

Chemical(intracellular

messengers)

Electrical(membrane

ion channels)

Physiologicalfunctions

Neurotransmitter-based classification

1- Cholinergic, 2- Adrenergic, and 3- Dopaminergic

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1- Cholinergic transmitter

• It means related to the neurotransmitter Acetylcholine.• The parasympathetic nervous system is entirely cholinergic.

Neuromuscular junctions, preganglionic neurons of the sympathetic nervous system, and the sweat glands

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Definition of Agonist and Antagonist

Agonist: A structural analog that is capable of stimulating a biological response.

Antagonist: A receptor-specific blocker (e.g., enzyme inhibitor) or a physiologic agent (e.g., hormone), that prevents the action of another molecule.

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Mode of Action

Direct-acting: Molecule that physically binds to the target for its effect.

Example: ACh activates cholinergic receptors.

Indirect-acting: Molecule that exerts effect on the target by interacting with another molecule.

Example:neostigmine blocks AchE, causing Ach accumulation.

Acetylcholine (ACh) • Cholinergic neurotransmitter.• Parasympathomimetic.• Muscarinic action.(M3)

Sites of release: Preganglionic synapses of both sympathetic and

parasympathetic ganglia. Parasympathetic postganglionic neuroeffector junctions. All somatic motor end-plates on skeletal muscles.

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Muscarinic Autonomic Effects of Ach

• Affect on gatsrtointestinal tract (GIT) as follow• 1- Motility (Increase contraction)• 2- Secretion (increase)• 3- Sphincters (relaxation)

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Muscarinic Actions

• The “Muscarinic Actions” -- Similar to those of parasympathetic stimulation

• • (M1): CNS, PNS, gastric parietal cells • • (M2): conducting tissue • • (M3): exocrine glands; smooth muscle

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Action of acetylcholine on smooth muscle.

• Contraction of smooth muscle by acetylcholine is mediated by activation of muscarinic receptors M2 and M3 subtypes.

• Acetylcholine (ACh) has virtually no systemic therapeutic applications because its actions are diffuse, and its hydrolysis, catalyzed by both acetylcholinesterase (AChE) and plasma butyrylcholinesterase, is rapid.

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Dose-Response Curve

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Apparatus

Valve

(Wash)

valve

H2O

physiogragh

Tyroide

Solution

Intestine part

25 ml

Oxygen supply

NaCl:

Isotenicity

CaCl2:

Contraction of muscle

Glucose:

Energy

NaHCO3:

PH

MgCL2:

relaxation

Why Tryroid Solution:

• 1- To maintain the muscle alive throughout the experiment.

• 2- To maintain the same environmental condition for the cells inside the animal (In vivo) as outside the animal (In vitro).

Why small intestine?

• 1- Easy handling in the lab.• 2- Good model to study the effects of

cholinergic drugs.• 3- Longitudinal muscle of guinea pig intestine

contains muscarinic receptors of which M2 and M3 subtypes.

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Definition of dose- response curve:

• It is a relationship between dose & response which describes the change in effect on an organ caused by differing levels of exposure (or doses) to a stressor (usually a chemical) after a certain exposure time.

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Dose – Response Curve

• It is a relationship between Dose and (Response %)• From this curve we can see :

Potency (a measure of the activity of a drug in a biological system)

Efficacy (the capacity to produce an effect)Therapeutic index (dose of a drug for 50% of the population

divided by the minimum effective dose for 50% of the population ED 50 :dose in pharmacology is the amount of drug that produces a therapeutic response in 50% of the people taking it

Procedure1- Cut 1 Cm from Guine pig small intestine and hang it in the organ bath which has tyroid solution.2- Use MP36 to measure the contraction of the intestine inside the organ bath.3- Add 0.1 ml Acetylcholine (Ach) (0.1 %) to the intestine which in the organ bath and record the response then stop the MP36 and make washing for the tyroid in the organ bath. 4- Add 0.2 ml of Ach and record the response and then wash.3- Add 0.4, 0.8, 1.6,>>>>. Till get maximum response for the contraction of the intestine as showing in next slide.4- Tabulate the relationship between the dose and response (cm) and % of response .5- Make histogram between the dose and % response to get ED50 as shown .

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Dose – Response Curve

D + R DR complex Response

cm

0.1ml 0.2ml 0.4ml 0.8ml 1.6ml

wash

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Dose – Response Curve

Response %

)x/ max*( 100

Response (cm)

Dose )ml(

33.3 1 0.1

60 1.8 0.2

83.3 2.5 0.4

100 3 0.8

100 3 1.6

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ED 50 = xxx ml